Ternary and quaternary phase diagrams: key tools for chiral resolution through solution cocrystallization

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

“…Because hydrogen bonding is one of the main forces to form co-crystal, co-crystal can not be formed in solvents with strong hydrogen bonding between molecules. Springuel et al [ 37 , 46 ] reported that mandelic acid and LEV formed co-crystal in acetonitrile. Our preliminary study also showed that, under the same experimental conditions, levetiracetam and 3-ClMA could not form co-crystal precipitated solid in methanol, ethanol, and isopropanol, and only a small amount of solid could be obtained when ethyl acetate was used as solvent for co-crystal resolution.…”

“…Our preliminary study also showed that, under the same experimental conditions, levetiracetam and 3-ClMA could not form co-crystal precipitated solid in methanol, ethanol, and isopropanol, and only a small amount of solid could be obtained when ethyl acetate was used as solvent for co-crystal resolution. In this work, combined with the research of Springuel et al [ 37 , 46 ], the resolution of mandelic acid derivatives by LEV used acetonitrile as solvent.…”

“… Effect of solvent amount on the resolution of 3-ClMA by LEV (the mole fraction of acetonitrile refers to the ratio of the moles of acetonitrile to the sum of the moles of acetonitrile and raw materials, mol%) [ 37 , 46 ]. (LEV = 2.84 mmol; 3-ClMA = 2.32 mmol; crystallization temperature = −15 °C; equilibrium time = 12 days).…”

Structural similarity in chiral-achiral multi-component crystals

“…The creation of co-crystals in this case offers an alternative solid form and studies have been undertaken to identify the feasibility of using chiral coformers for selective resolution. [8][9][10] This method, as with salt formation, requires chirally pure co-former material to resolve the desired molecule as the interactions and crystal packing for an achiral co-former would be expected to be equal with either the R or S enantiomer. This can lead to a limited set of potential co-formers which may or may not co-crystallise with the material under study.…”

Diversity in a simple co-crystal: racemic and kryptoracemic behaviour

“…[1][2][3][4] Co-crystallization is one approach that has garnered interest since the generation of families of related materials provides an opportunity to modulate targeted physicochemical properties over a broad range. For this reason it has been explored in a variety of fields including pharmaceuticals, [5][6][7][8][9] nutraceuticals, [10][11][12] agrochemicals, 13,14 explosives, [15][16][17][18] solid-state photochemistry, 19,20 chiral resolution, [21][22][23] etc. Recently, the US Food and Drug Administration recognised the importance of co-crystals and issued guidelines for their use in the pharmaceutical sector.…”